ABSTRACT Obesity and physical inactivity are both related to increased mortality and morbidity in conjunction with increased risk for the development of type 2 diabetes, the metabolic syndrome and cardiovascular disease. We propose to examine if physical activity will provide an additive effect of reducing risk factors for CVD in an extremely at risk population (very obese individuals) following bariatric weight loss surgery. Preliminary data from each of our research groups has indicated that an inefficient use of fatty acids and diminished oxidative capacity is strongly associated with the pathophysiology of insulin resistance of obesity. Thus impaired fatty acid utilization and insulin resistance are both characteristic of the metabolic inflexibility in obesity. The prevailing paradigm is that [unreadable]mitochondrial dysfunction[unreadable] underpins metabolic inflexibility and thus directly contributes to the pathophysiology of skeletal muscle insulin resistance. While this hypothesis is attractive, it has not been experimentally proven. Although weight loss itself can improve insulin resistance, it does little, if anything to improve mitochondria function or to promote more efficient utilization of fatty acids in obesity. Moreover, physical activity may promote positive effects on mitochondria function, fatty acid metabolism and insulin resistance independent of weight loss. We propose to employ a randomized controlled physical activity intervention trial in a group of patients following their weight loss surgery. Our primary hypotheses are that the combination of weight loss + physical activity will provide additive (and thus independent) positive effects on: 1) weight loss and body composition;2) metabolic risk factors such as insulin action and other markers of the metabolic syndrome;and 3) markers of mitochondria function and the capacity for efficient fat utilization by muscle. These findings will be novel and relevant to treating obesity, as morbidly obese individuals are likely genetically and environmentally predisposed towards a negative metabolic status and a sedentary lifestyle;it is not evident if physical activity can provide an additional positive stimulus to dramatic weight loss in these patients. Investigating the role of increased physical activity following surgery-induced weight loss is critical to our understanding of the most effective strategies to treat obesity and its associated conditions. Information emanating from this study would thus help to determine the most effective treatments to prevent weight regain and to improve outcomes of these patients following surgery. PROJECT NARRATIVE Obesity and physical inactivity are both related to increased mortality and morbidity in conjunction with increased risk for the development of type 2 diabetes, the metabolic syndrome and cardiovascular disease. We propose to examine if physical activity will provide an additive effect of reducing risk factors for CVD in an extremely at risk population (very obese individuals) following bariatric weight loss surgery. Preliminary data from each of our research groups has indicated that an inefficient use of fatty acids and diminished oxidative capacity is strongly associated with the pathophysiology of insulin resistance of obesity. Thus impaired fatty acid utilization and insulin resistance are both characteristic of the metabolic inflexibility in obesity. The prevailing paradigm is that [unreadable]mitochondrial dysfunction[unreadable] underpins metabolic inflexibility and thus directly contributes to the pathophysiology of skeletal muscle insulin resistance. While this hypothesis is attractive, it has not been experimentally proven. Although weight loss itself can improve insulin resistance, it does little, if anything to improve mitochondria function or to promote more efficient utilization of fatty acids in obesity. Moreover, physical activity may promote positive effects on mitochondria function, fatty acid metabolism and insulin resistance independent of weight loss. We propose to employ a randomized controlled physical activity intervention trial in a group of patients following their weight loss surgery. Our primary hypotheses are that the combination of weight loss + physical activity will provide additive (and thus independent) positive effects on: 1) weight loss and body composition;2) metabolic risk factors such as insulin action and other markers of the metabolic syndrome;and 3) markers of mitochondria function and the capacity for efficient fat utilization by muscle. These findings will be novel and relevant to treating obesity, as morbidly obese individuals are likely genetically and environmentally predisposed towards a negative metabolic status and a sedentary lifestyle;it is not evident if physical activity can provide an additional positive stimulus to dramatic weight loss in these patients. Investigating the role of increased physical activity following surgery-induced weight loss is critical to our understanding of the most effective strategies to treat obesity and its associated conditions. Information emanating from this study would thus help to determine the most effective treatments to prevent weight regain and to improve outcomes of these patients following surgery.